rs764896402
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_133510.4(RAD51B):c.84G>A(p.Gln28=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000962 in 1,455,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
RAD51B
NM_133510.4 splice_region, synonymous
NM_133510.4 splice_region, synonymous
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.27
Genes affected
RAD51B (HGNC:9822): (RAD51 paralog B) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are evolutionarily conserved proteins essential for DNA repair by homologous recombination. This protein has been shown to form a stable heterodimer with the family member RAD51C, which further interacts with the other family members, such as RAD51, XRCC2, and XRCC3. Overexpression of this gene was found to cause cell cycle G1 delay and cell apoptosis, which suggested a role of this protein in sensing DNA damage. Rearrangements between this locus and high mobility group AT-hook 2 (HMGA2, GeneID 8091) have been observed in uterine leiomyomata. [provided by RefSeq, Mar 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PP5
?
Variant 14-67823627-G-A is Pathogenic according to our data. Variant chr14-67823627-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 221910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51B | NM_133510.4 | c.84G>A | p.Gln28= | splice_region_variant, synonymous_variant | 2/11 | ENST00000471583.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51B | ENST00000471583.6 | c.84G>A | p.Gln28= | splice_region_variant, synonymous_variant | 2/11 | 1 | NM_133510.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 151906Hom.: 0 Cov.: 32 FAILED QC
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GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248200Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134088
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GnomAD4 exome AF: 0.00000962 AC: 14AN: 1455598Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8AN XY: 724074
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GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 151906Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74170
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Cancer Genetics and Family Consultants, Athens Medical Center | Dec 12, 2015 | The mutation was observed in one patient with high grade DCIS, Her2 positive and strong family history (mother with bilateral breast cancer and maternal aunt with breast cancer and thyroid cancer). The same mutation has been described as a leaky splicing variant of the RAD51B (PMID:26898890). First time in Greece, it has been observed among 164 patients with breast and ovarian cancers tested in the our clinic. We consider this variant to be likely pathogenic. - |
Likely pathogenic, no assertion criteria provided | research | Dr. Peter K. Rogan Lab, Western University | Dec 22, 2015 | Sequenced patient with familial breast cancer - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variant is change of the last base in exon 2 of the RAD51B gene, which is conserved in the human genome and other genomes. Although it does not lead to an amino acid change, it is expected that this alteration causes improper sRNA splicing and deletion of the entire exon. Thus the protein produced by one allele is expected to be truncated and non-functional. This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 221910). - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at